Perspectives on the model-based approach to proton therapy trials: A retrospective study of a lung cancer randomized trial

• Published in: Radiotherapy and oncology Vol. 147; pp. 8 - 14
• Main Authors: McNamara, Aimee L., Hall, David C., Shusharina, Nadya, Liu, Amy, Wei, Xiong, Ajdari, Ali, Mohan, Radhe, Liao, Zhongxing, Paganetti, Harald
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.06.2020
• Subjects: Humans; Lung Neoplasms - radiotherapy; Model-based approach; Non-small cell lung cancer; NTCP; Proton Therapy; Protons; Radiation Pneumonitis; Radiotherapy Planning, Computer-Assisted; Randomized clinical trial; Retrospective Studies; Model-based approach; Randomized clinical trial; Proton therapy; Non-small cell lung cancer; NTCP
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2020.02.022

•Model-based trial applied retrospectively to randomized lung cancer trial.•NTCP differences between modalities were too small to support a model-based trial.•Photon based NTCP model for radiation pneumonitis may not apply to proton patients.•Applicability of NTCP models may be endpoint and treatment site dependent. The goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. A model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. Uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.